Indole containing, 2-thienyl-1,2,3,6-tetrahydropyridyls and their pharmaceutical use

ABSTRACT

Indole derivatives of the general formula I ##STR1## in which Ind is a 3-indolyl radical which can be substituted once or twice by alkyl, O-alky, S-alkyl, SO-alkyl, SO 2  -alkyl, OH, F, Cl, Br, CF 3  and/or CN or by a methylenedioxy group, A is --(CH 2 ) 4  -- or --CH 2  --L--CH 2  CH 2  --, L is --S--, --SO-- or --SO 2  --, and Th is a 2-- or 3-thienyl radical, and in which the alkyl groups each have 1-4 C atoms, and their physiologically acceptable acid addition salts exhibit effects on the central nervous system.

The present invention relates to new indole derivatives.

SUMMARY OF THE INVENTION

It is an object of this invention to provide new compounds which can be used for the production of medicaments.

Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.

These objects have been achieved by providing the new indoles of Formula I ##STR2## in which Ind is a 3-indolyl radical which can be substituted once or twice by alkyl, O-alkyl, S-alkyl, SO-alkyl, SO₂ -alkyl, OH, F, Cl, Br, CF₃ and/or CN or by a methylenedioxy group, A is --(CH₂)₄ -- or --CH₂ --L--CH₂ CH₂ --, L is --S--, --SO-- or ---SO₂ --, and Th is a 2- or 3-thienyl radical, and in which the alkyl groups each have 1-4 C atoms, and their physiologically acceptable acid addition salts.

DETAILED DISCUSSION

It was found that the compounds of the Formula I and their physiologically acceptable acid addition salts have valuable pharmacological properties. Thus, in particular, they exhibit effects on the central nervous system, especially dopamine-stimulating (anti-parkinsonism) effects. Specifically, the compounds of the Formula I induce contralateral turning behavior in rats with hemiparkinsonism (which may be demonstrated by the method of Ungerstedt et al., Brain Res. 24, (1970), 485-493) and they inhibit the binding of tritiated dopamine agonists and antagonists to striatal receptors (which may be demonstrated by the method of Schwarcz et al., J. Neurochemistry, 34, (1980), 772-778 and Creese et al., European J. Pharmacol., 46, (1977), 377-381). In addition, the compounds inhibit the linguomandibular reflex in the anaesthetized rat (which may be demonstrated by methods derived from Barnett et al., European J. Pharmacol. 21, (1973), 178-182, and from Ilhan et al., European J. Pharmacol. 33, (1975) 61-64). Moreover, analgesic effects are displayed.

Thus, compounds of the formula I and their physiologically acceptable acid addition salts can be used as active compounds in medicaments and also as intermediate products for the preparation of other active compounds in medicaments.

The invention relates to the indole derivatives of the formula I and their physiologically acceptable acid addition salts.

In the radicals Ind, alkyl is preferably methyl, but is also ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl. O-Alkyl is preferably methoxy, but also ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy or tert.-butoxy. S-Alkyl is preferably methylthio, but is also ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec.-butylthio or tert.-butylthio. SO-Alkyl is preferably methylsulfinyl, but is also ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, sec.-butylsulfinyl or tert.-butylsulfinyl. SO₂ -Alkyl is preferably methylsulfonyl, but is also ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec.-butylsulfonyl or tert.-butylsulfonyl.

The radical Ind is, in particular, an unsubstituted 3-indolyl radical. However, if Ind is a substituted 3-indolyl radical, then it is preferably substituted once, in particular in the 2-, 5- or 6-position. Substitution in the 1-, 4- or 7-position is also possible. Preferred disubstituted 3-indolyl radicals are substituted in the 5,6-positions; disubstitution is also possible in the 1,2-, 1,4-, 1,5-, 1,6-, 1,7-, 2,4-, 2,5-, 2,6-, 2,7-, 4,5-, 4,6-, 4,7-, 5,7- or 6,7-positions. In all these cases the substituents can be identical or different.

Specifically, the preferred substituents in the benzene ring of the Ind radical are methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio, OH, F, Cl, Br, CF₃ and CN. Accordingly, some preferred meanings of the Ind radical are 3-indolyl, but also 1-, 2-, 4-, 5-, 6- or 7-methyl-3-indolyl, 1-, 2-, 4-, 5-, 6- or 7-ethyl-3-indolyl, 4-, 5-, 6- or 7-methoxy-3-indolyl, 4-, 5-, 6- or 7-ethoxy-3-indolyl, 4-, 5-, 6- or 7-methylthio-3-indolyl, 4-, 5-, 6- or 7-ethylthio-3-indolyl, 4-, 5-, 6- or 7-methyl-sulfinyl-3-indolyl, 4-, 5-, 6- or 7-methylsulfonyl-3-indolyl, 4-, 5-, 6- or 7-hydroxy-3-indolyl, 4-, 5-, 6- or 7-fluoro-3-indolyl, 4-, 5-, 6- or 7-chloro-3-indolyl, 4-, 5-, 6- or 7-bromo-3-indolyl, 4-, 5-, 6- or 7-trifluoromethyl-3-indolyl, 4-, 5-, 6- or 7-cyano-3-indolyl, 1,2-, 1,4-, 1,5-, 1,6-, 1,7-, 2,4-, 2,5-, 2,6-, 2,7-, 4,5-, 4,6-, 4,7-, 5,6-, 5,7- or 6,7-dimethyl-3-indolyl, 1-methyl-4-, -5-, -6- or -7-methoxy-3-indolyl, 1-methyl-4-, -5-, -6- or -7-fluoro-3-indolyl, 1-methyl-4-, -5-, -6- or -7-chloro-3-indolyl, 1-methyl-4-, -5-, -6 - or 7-bromo-3-indolyl, 1-methyl-4-, -5-, -6- or -7-trifluoromethyl-3-indolyl, 1-methyl-4-, -5-, -6- or -7-cyano-3-indolyl, 2-methyl-4-, -5-, -6- or -7-methoxy-3-indolyl 2-methyl-4-, -5-, -6- or -7-methylthio-3-indolyl, 2-methyl-4-, -5-, -6- or -7-fluoro-3-indolyl, 2-methyl-4-, -5-, -6- or -7-chloro-3-indolyl, 2-methyl-4-, -5-, -6- or -7-bromo-3-indolyl, 2-methyl-4-, -5-, -6- or -7-trifluoromethyl-3indolyl, 2-methyl-4-, -5-, -6- or -7-cyano-3-indolyl, 4-methyl-5-fluoro-3-indolyl, 5-fluoro-6- or -7-methyl-3-indolyl, 4-methyl-5-chloro-3-indolyl, 4-chloro-5-methyl-3-indolyl, 5-methyl-6- or -7 -chloro-3-indolyl, 5-chloro-6- or -7-methyl-3-indolyl, 4,5-, 4,6-, 4,7-, 5,6-, 5,7- or 6,7-dimethoxy-3-indolyl, 4,5-, 4,6-, 4,7-, 5,6-, 5,7-or 6,7-dichloro-3-indolyl, 4-trifluoromethyl-5-, -6- or -7-chloro-3-indolyl.

The group A is preferably --(CH₂)₄ --. The group L is preferably an S atom. Th is preferably a 2-thienyl radical.

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the meanings indicated above, in particular one of the preferred meanings indicated above Some preferred groups of compounds can be expressed by the following part formulae Ia to Ik which correspond to the formula I and wherein the radicals which are not specified have the meaning indicated for formula I, but wherein

in Ia, Ind is 3-indolyl, methyl-3-indolyl, dimethyl-3-indolyl, methoxy-3-indolyl, dimethoxy-3-indolyl, hydroxy-3-indolyl, dihydroxy-3-indolyl, fluoro-3-indolyl, chloro-3-indolyl, dichloro-3-indolyl, bromo-3-indolyl, cyano-3-indolyl or methylenedioxy-3-indolyl, the substituents preferably being in the 5- and/or 6-positions;

in Ib, Ind is 3-indolyl, 5- or 6-methyl-3-indolyl, 5,6-dimethyl-3-indolyl, 5- or 6-methoxy-3-indolyl, 5,6-dimethoxy-3-indolyl, 6-methylthio-3-indolyl, 6-hydroxy-3-indolyl, 5-chloro-3-indolyl or 5-fluoro-3-indolyl;

in Ic, Ind is 3-indolyl or 5,6-dimethoxy-3-indolyl;

in Id, A is --(CH₂)₄ --;

in Ie, A is --CH₂ --L--CH₂ CH₂ --;

in If, A is --CH₂ --S--CH₂ CH₂ --;

in Ig, Th is 2-thienyl;

in Ih, Ind is 3-indolyl, 5,6-dimethyl-3-indolyl, 6-methoxy-3-indolyl, 5,6-dimethoxy-3-indolyl, 6-methylthio-3-indolyl, 6-hydroxy-3-indolyl, 5-fluoro-3-indolyl or 5-chloro-3-indolyl, A is --(CH₂)₄ -- or --CH₂ --S--CH₂ CH₂ --, and Th is 2-thienyl;

in Ii, Ind is 3-indolyl or 5,6-dimethoxy-3-indolyl, A is --(CH₂)₄ -- or --CH₂ --S--CH₂ CH₂ --, and Th is 2-thienyl;

in Ij, Ind is 3-indolyl, A is --(CH₂)₄ -- or --CH₂ --S--CH₂ CH₂ -- and Th is 2-thienyl;

in Ik, Ind is 3-indolyl or 5,6-dimethoxy-3-indolyl, A is --(CH₂)₄ -- and Th is 2-thienyl.

The compounds of the formula I can have one or more asymmetric carbon atoms. Thus they can exist as racemates and, if several asymmetric carbon atoms are present, they can also exist as mixtures of several racemates and in various optically active forms.

The invention also relates to a process for the preparation of the compounds of the formula I and their physiologically acceptable acid addition salts, which is characterized in that a compound of the general formula II

    Ind--A--X.sup.1                                            II

in which X¹ is X or NH₂, and X is Cl, Br, I, OH or a reactive derivative of an OH group, and Ind and A have the indicated meanings, is reacted with a compound of the general formula III ##STR3## in which X² and X³ can be identical or different and, when X¹ is NH₂, are each X, otherwise are together NH, and Th has the indicated meaning, or in that a compound which otherwise corresponds to the formula I but, in place of one or more hydrogen atoms, contains one or more reducible group(s) and/or one or more additional C--C and/or C--N bond(s) is treated with a reducing agent, or in that a compound which otherwise corresponds to the formula I but, in place of one or more hydrogen atoms, contains one or more group(s) which can be eliminated by solvolysis is treated with a solvolysing agent, or in that a compound of the formula IV ##STR4## in which one radical E is X, CN or NH₂, the other radical E is H, and Ind, A, Th and X have the indicated meanings, is treated with an agent eliminating HE, and/or in that, where appropriate, in a compound of the formula I, a thioether group is oxidized to an SO group or SO₂ group, or an SO group is oxidized to an SO₂ group, and/or an alkoxy group is cleaved to form an OH group, and/or in that a base of the formula I which has been obtained is converted, by treatment with an acid, into one of its physiologically acceptable acid addition salts.

The preparation of the compounds of the formula I is otherwise carried out by methods known per se as are described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York), namely under reaction conditions as are known and suitable for the reactions mentioned. Use can also be made in these preparations of variants known per se which are not mentioned in more detail here.

The starting materials can, if desired, also be formed in situ in such a manner that they are not isolated from the reaction mixture but are immediately reacted further to give the compounds of the formula I.

In the indole derivatives of the formula II, X¹ is preferably X; accordingly, in the compounds of the formula III, X² and X³ together are preferably NH. The radical X is preferably Cl or Br; however, it can also be I, OH or a reactive derivative of an OH group, in particular alkylsulfonyloxy having 1-6 (for example methanesulfonyloxy) or arylsulfonyloxy having 6-10 C atoms (for example benzenesulfonyloxy, p-toluenesulfonyloxy, 1- or 2-naphthalenesulfonyloxy).

Accordingly, the indole derivatives of the formula I can be obtained, in particular, by reaction of the compounds of the formulae Ind-A-Cl or Ind-A-Br with tetrahydropyridine derivatives of the formula III, wherein X² and X³ together are a NH group (denoted IIIa in the following text).

Some of the compounds of the formulae II and III are known; the unknown compounds of the formulae II and III can easily be prepared in analogy to the known compounds.

Compounds of the formula II (A=--CH₂ --S--CH₂ CH₂ --) can be prepared from, for example, gramine and thiols of the formula HS--CH₂ CH₂ X¹, for example HS--CH₂ CH₂ OH. The sulfoxides and sulfones of the formulae Ind--CH₂ --SO--CH₂ CH₂ X¹ and Ind--CH₂ --SO₂ --CH₂ CH₂ X¹ are accessible by oxidation of the thioethers of the formula Ind--CH₂ --S--CH₂ CH₂ X¹. Primary alcohols of the formula II (X¹ =OH), for example Ind--(CH₂)₄ --OH or Ind--CH₂ --S--CH₂ CH₂ OH, can be obtained by, for example, reduction of the corresponding carboxylic acids or their esters. Treatment with thionyl chloride, hydrogen bromide, phosphorus tribromide or similar halogen compounds provides the corresponding halides of the formula Ind--A--Hal. The corresponding sulfonyloxy compounds can be obtained from the alcohols Ind--A--OH by reaction with the corresponding sulfonyl chlorides.

The iodo compounds of the formula Ind--A--I can be prepared by, for example, the action of potassium iodide on the relevant p-toluenesulfonic esters, and the amines of the formula Ind--A--NH₂ can be prepared from, for example, the halides with potassium phthalimide or by reduction of the corresponding nitriles.

The tetrahydropyridine derivatives IIIa can be obtained by, for example, reacting 4-piperidone with organometallic compounds of the formula M--Th (in which M is a Li atom or MgHal, and Hal is Cl, Br or I), followed by hydrolysis to give the corresponding 4-Th-4-hydroxypiperidines, and subsequent dehydration. Compounds of the formula III (X² and X³ each=X) can be prepared by, for example, reduction of 3-Th-2-pentene-1,5-dioic diesters to give 3-Th-2-pentene-1,5-diols and, where appropriate, subsequent reaction with SOCl₂ or PBr₃.

The reaction of the compounds II and III takes place by methods as are known from the literature for the alkylation of amines. It is possible to fuse the components together in the absence of a solvent, if appropriate in a closed tube or in an autoclave. However, it is also possible to react the compounds in the presence of an inert solvent. Examples of suitable solvents are hydrocarbons, such as benzene, toluene or xylene; ketones, such as acetone or butanone; alcohols, such as methanol, ethanol, isopropanol or n-butanol; ethers, such as tetrahydrofuran (THF) or dioxane; amides, such as dimethylformamide (DMF) or N-methylpyrrolidone; nitriles, such as acetonitrile, and, if appropriate, mixtures of these solvents with one another or mixtures with water. The addition of an acid-binding agent, for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another weak acid salt of the alkali metals or alkaline earth metals, preferably of potassium, sodium or calcium, or the addition of an organic base, such as triethylamine, dimethylaniline, pyridine or quinoline or an excess of the amine component Ind--A--NH₂ or the piperidine derivative of the formula IIIa can be advantageous.

The reaction time depends on the conditions used and is between a few minutes and 14 days, and the reaction temperature is between about 0° and 150°, normally between 20° and 130°.

Furthermore, it is possible to obtain a compound of the formula I by treating a precursor which, in place of hydrogen atoms, contains one or more reducible group(s) and/or one or more additional C--C and/or C--N bond(s) with reducing agents, preferably at temperatures between -80° and +250° in the presence of at least one inert solvent.

Reducible groups (replaceable by hydrogen) are, in particular, oxygen in a carbonyl group, hydroxyl, arylsulfonyloxy (for example p-toluenesulfonyloxy), N-benzenesulfonyl, N-benzyl or O-benzyl).

It is possible in principle to convert compounds which contain only one of the abovementioned groups or additional bonds or those compounds which contain together two or more of the abovementioned groups or additional bonds into a compound of the formula I by reduction. Nascent hydrogen or complex metal hydrides, but also reduction by the method of Wolff-Kishner, is preferably used for this purpose.

Preferred starting materials for the reduction correspond to the formula V

ti Ind'--A'--Q--Th V

in which Ind' is a 3-indolyl radical which can be substituted once or twice in the 1-position by alkyl, O-alkyl, S-alkyl, SO-alkyl, SO₂ -alkyl, OH, F, Cl, Br, CF₃, CN and/or O-benzyl or by a methylenedioxy group and/or by an arylsulfonyl group or a benzyl group, A' is a --(CH₂)₄ -- or --CH₂ --L--CH₂ CH₂ -- chain in which one or more --CH₂ -- group(s) can be replaced by --CO-- group(s), and/or one or more hydrogen atoms can be replaced by OH groups, Q is ##STR5## and An.sup.⊖ is an anion of a strong acid, but in which it is not possible at the same time for Ind' to be Ind, A' to be A and Q to be ##STR6##

In the compounds of the formula V, A' is preferably --(CH₂)₃ --CO--CH₂ --, or --CH₂ --L--CH₂ --CO--, but is also preferably --CH₂ --CO--(CH₂)₂ -- or --CO--(CH₂)₃ --.

Compounds of the formula V can be prepared by, for example, reacting 4-Th-1,2,3,6-tetrahydropyridines or 4-Th-pyridines with a compound of the formula VI

    Ind'--A'--X.sup.1                                          VI

in which Ind', A' and X¹ have the indicated meanings, under the conditions indicated above for the reaction of II with III.

Amides of the formula V (A'=--(CH₂)₃ --CO-- or --CH₂ --L--CH₂ --CO--, Q= ##STR7## which are preferred as starting materials for the reduction, are successfully prepared from, for example, the free carboxylic acids of the formulae Ind'--(CH₂)₃ --COOH or Ind'--CH₂ --L--CH₂ --COOH and tetrahydropyridines of the formula IIIa in the presence of a dehydrating agent, such as carbonyldiimidazole or dicyclohexylcarbodiimide, in one of the indicated inert solvents, preferably THF.

When nascent hydrogen is used as the reducing agent for the preparation of the compounds of the formula I by reduction, this can be produced by, for example, treatment of metals with weak acids or with bases. Thus, for example, a mixture of zinc with alkali metal hydroxide solution or of iron with acetic acid can be used.

It is also suitable to use sodium or another alkali metal in an alcohol, such as ethanol, isopropanol, butanol, amyl or isoamyl alcohol or phenol. It is also possible to use an aluminum/nickel alloy in an aqueous alkaline solution, optionally with the addition of ethanol. Sodium amalgam or aluminum amalgam in aqueous alcoholic or aqueous solution are also suitable to produce nascent hydrogen. The reaction can also be carried out in heterogeneous phases, it being preferable to use an aqueous and a benzene or toluene phase.

Moreover, it is possible to use with particular advantage complex metal hydrides, such as LiAlH₄, NaBH₄, diisobutylaluminium hydride or NaAl(OCH₂ CH₂ OCH₃)₂ H₂, and diborane, as the reducing agent, if desired with the addition of catalysts, such as BF₃, AlCl₃ or LiBr. Solvents which are particularly suitable for this purpose are ethers, such as diethyl ether, di-n-butyl ether, THF, dioxane, diglyme or 1,2-dimethoxyethane, and hydrocarbons, such as benzene. For reduction with NaBH₄, alcohols, such as methanol or ethanol, but also water and aqueous alcohols, are primarily suitable as the solvent. Reduction by these methods is preferably carried out at temperatures between -80° and +150°, in particular between about 0° and about 100°.

It is possible particularly advantageously to reduce --CO-- groups in amides with LiAlH₄ in THF at temperatures between about 0° and 66° to give CH₂ groups. During this, arylsulfonyl protective groups located in the 1-position of the indole ring can simultaneously be reductively eliminated.

It is possible to reduce the pyridinium salts of the formula V (in which Q is ##STR8## and An is preferably Cl or Br) to give compouns of the formula I using, for example, NaBH₄ in water, methanol or ethanol or in mixtures of these solvents, with the addition, if desired, of a base, such as NaOH, at temperatures between about 0° and 80°.

N-Benzyl groups can be reductively eliminated using sodium in liquid ammonia.

Moreover, it is possible to reduce one or more carbonyl groups to CH₂ groups by the method of Wolff-Kishner, for example, by treatment with anhydrous hydrazine in absolute ethanol under pressure at temperatures between about 150° and 250°. Sodium alcoholate is advantageously used as a catalyst. The reduction can also be modified by the method of Huang-Minlon by carrying out the reaction with hydrazine hydrate in a high-boiling solvent which is miscible with water, such as diethylene glycol or triethylene glycol, in the presence of alkali, such as sodium hydroxide. As a rule, the reaction mixture is boiled for about 3-4 hours. The water is then distilled off and the hydrazone formed is decomposed at temperatures up to about 200°. The Wolff-Kishner reduction can also be carried out with hydrazine in dimethyl sulfoxide at room temperature.

Compounds which otherwise correspond to formula I but, in place of one or more H atoms, contain one or more group(s) which can be eliminated by solvolysis can be solvolyzed, in particular hydrolyzed, to give compounds of the formula I. The starting materials for the solvolysis can be obtained by, for example, reaction of IIIa with compounds which correspond to the formula II (X¹ =X) but, in place of one or more H atoms, contain one or more group(s) which can be eliminated by solvolysis. Thus, 1-acylindole derivatives (corresponding to the formula I but containing an acyl group, preferably an alkanoyl, alkylsulfonyl or arylsulfonyl group each having up to 10 C atoms, such as methane-, benzene- or p-toluenesulfonyl in the 1-position of the Ind radical) can be hydrolyzed to give the corresponding indole derivatives which are unsubstituted in the 1-position of the indole ring, for example in acid, but better in neutral or alkaline medium at temperatures between 0° and 200°. Sodium, potassium or calcium hydroxide, sodium or potassium carbonate or ammonia are preferably used as the basic catalysts. The solvents which are preferably chosen are water, lower alcohols, such as methanol or ethanol, ethers, such as THF or dioxane, sulfones, such as tetramethylenesulfone or their mixtures, especially the mixtures containing water. Hydrolysis can even take place just on treatment with water alone, in particular at the boiling point.

Moreover, compounds of the formula I can be obtained by eliminating HE from compounds of the formula IV to form a double bond. According to the definition of E, this can comprise, for example, eliminating hydrogen halide, water (dehydration), a carboxylic acid or another acid, ammonia or HCN. The starting materials of the formula IV can be obtained by, for example, reaction of II (X¹ =X) with a compound of the formula VII ##STR9## in which E and Th have the indicated meanings. If one of the radicals E is Hal, this substituent can easily be eliminated under basic reaction conditions. The following can be used as bases: alkali metal hydroxides, alkali metal carbonates, alcoholates, such as, for example, potassium tert.-butylate, amines, such as, for example, dimethylaniline, pyridine, collidine or quinoline; the solvent used is, for example, benzene, toluene, cyclohexane, methanol, dioxane, THF or tert.-butanol. The amines used as bases can also be employed in excess as the solvent. If one of the radicals E is an OH group, then acids, such as acetic acid, hydrochloric acid or mixtures of the two, are preferably used as the agent to split off water. The addition of a solvent (for example water or ethanol) can be advantageous. The elimination of acyl, alkylsulfonyl and alkoxysulfonyloxy or amino radicals can be carried out under similar conditions. An elimination of sulfonic acid radicals, for example mesylates or tosylates, takes place under mild conditions by boiling in DMF or dimethyl sulfoxide with alkali metal carbonates, for example Li₂ CO₃ or with potassium acetate. Ammonia can be eliminated by just heating the salts of the corresponding amino compounds (especially the 4-amino derivatives). In a similar manner, HCN can be eliminated from compounds of the formula IV (one group E=CN) by heating. The elimination of HE from IV generally takes place at temperatures between about 0° and about 250°, preferably between 50° and 200°.

Furthermore, the thioether group in a thioether of the formula I can be oxidized to an SO group or to an SO₂ group, or the SO group in a sulfoxide of the formula I can be oxidized to a SO₂ group. The thioether or sulfoxide groups to be oxidized can be present in the group A and/or as substituents in the radical Ind. If the intention is to obtain the sulfoxides, then the oxidation is carried out, for example, with hydrogen peroxide, peracids, such as m-chloroperbenzoic acid, Cr(VI) compounds, such as chromic acid, KMnO₄, 1-chlorobenzotriazole, Ce(IV) compounds, such as (NH₄)₂ Ce(NO₃)₆, negatively substituted aromatic diazonium salts, such as o- or p-nitrophenyldiazonium chloride, or electrolytically under relatively mild conditions and at relatively low temperatures (about -80° to +100°). If, on the other hand, the intention is to obtain the sulfones (from the thioethers or the sulfoxides), then the same oxidizing agents are used under more forcing conditions and/or in excess and, as a rule, at higher temperatures. It is possible in these reactions for the customary inert solvents to be present or absent. Examples of suitable inert solvents are water, aqueous mineral acids, aqueous alkali metal hydroxide solutions, lower alcohols, such as methanol or ethanol, esters, such as ethyl acetate, ketones, such as acetone, lower carboxylic acids, such as acetic acid, nitriles, such as acetonitrile, hydrocarbons, such as benzene, and chlorinated hydrocarbons, such as chloroform or CCl₄. A preferred oxidizing agent is 30% aqueous hydrogen peroxide. On using the calculated amount in solvents such as acetic acid, acetone, methanol, ethanol or aqueous sodium hydroxide solution at temperatures between -20° and 100°, this leads to the sulfoxides, while in excess at higher temperatures, preferably in acetic acid or in a mixture of acetic acid and acetic anhydride, this leads to the sulfones.

Ethers of the formula I in which the radical Ind is substituted once or twice by O-alkyl can be cleaved by methods which are known from the literature, the corresponding hydroxyl derivatives being produced. For example, the ethers can be cleaved by treatment with HBr or HI in aqueous or acetic acid solution, by heating with Lewis acids, such as AlCl₃ or boron trihalides, or by fusing with pyridine or aniline hydrohalides, preferably pyridine hydrochloride, at about 150°-250°.

A base of the formula I which has been obtained can be converted into the relevant acid addition salt using an acid. Acids which provide physiologically acceptable salts are suitable for this reaction. Thus, inorganic acids can be used, for example, sulfuric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, nitric acid, sulfamic acid, but also organic acids, specifically aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemonosulfonic acids and naphthalenedisulfonic acids and lauryl sulfuric acid.

It is possible, if desired, to liberate the free bases of the formula I from their salts by treatment with strong bases, such as sodium or potassium hydroxide or sodium or potassium carbonate.

The invention also relates to the use of the compounds of the formula I and their physiologically acceptable salts for the preparation of pharmaceutical formulations, in particular by non-chemical means. For this purpose, it is possible to convert them into a suitable dosage form together with at least one vehicle or auxiliary and, where appropriate, combined with one or more other active compound(s).

The invention also relates to agents, especially pharmaceutical formulations, containing at least one compound of the formula I and/or one of its physiologically acceptable salts. These formulations can be employed as medicaments in human or veterinary medicine. Suitable vehicles are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and which do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatine, carbohydrates, such as lactose or starch, magnesium stearate, talc and vaseline. In particular, tablets, coated tablets, capsules, syrups, liquids, drops or suppositories are used for enteral administration, solutions, preferably oily or aqueous solutions, but also suspensions, emulsions or implants are used for parenteral administration, and ointments, creams or powders are used for topical application. It is also possible to freeze-dry the new compounds and use the lyophilizates obtained, for example, for the preparation of products for injection.

The indicated formulations can be sterilized and/or contain auxiliaries, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts to modify the osmotic pressure, buffer substances, dyes, flavorings and/or aromatic substances. If desired, they can also contain one or more other active compounds, for example one or more vitamins.

The invention also relates to the use of the compounds of the formula I and their physiologically acceptable salts for the therapeutic treatment of the human or animal body and for the control of illnesses, especially of parkinsonism, of extrapyramidal disturbances associated with neuroleptic therapy, of depression and/or psychosis and of side effects of-treatment for hypertension (for example with α-methyldopa). The compounds can also be used in endocrinology and gynaecology, for example for the therapy of acromegaly, hypogonadism, secondary amenorrhoea, premenstrual syndrome, undesired puerperal lactation and generally as prolactin inhibitors, also for the therapy of cerebral disturbances (for example migraine) and especially in geriatrics, similar to certain ergot alkaloids.

For these purposes, as a rule, the substances according to the invention are administered in analogy to known and commercially available products (for example bromocriptine and dihydroergocornine), preferably in doses between about 0.2 and 500 mg, in particular between 0.2 and 50 mg per dosage unit. The daily dose is preferably between about 0.001 and 10 mg/kg of body weight. In this context, the low doses (about 0.2 to 1 mg per dosage unit; about 0.001 to 0.005 mg/kg of body weight) are particularly suitable for use as agents for migraine; doses between 10 and 50 mg per dosage unit are preferred for the other indications. Preferred dose ranges for specific indications are as follows: paprkinsonism 1 to 200, preferably 40 to 100; dyskinesia 40 to 100; psychosis, for example schizophrenia, 2 to 20; acromegaly 2 to 50 mg per dosage unit. However, the specific dose for each particular patient depends on a wide variety of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the timing and mode of administration, on the rate of excretion, and on medicaments used in combination and the severity of the particular disorder to which the therapy is applied. Oral administration is preferred.

The chemical reactions described above are generally disclosed in terms of their broadest application to the preparation of the compounds of this invention. Occasionally, the reactions may not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifications known to those skilled in the art, e.g., by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, etc., or other reactions disclosed herein or otherwise conventional, will be applicable to the preparation of the corresponding compounds of this invention. In all preparative methods, all starting materials are known or readily preparable from known starting materials.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. In the following example(s), all temperatures are set forth uncorrected in degrees Celsius; unless otherwise indicated, all parts and percentages are by weight.

In the examples which follow, "usual work-up" denotes:

Water is added if necessary, the mixture is extracted with an organic solvent, such as toluene, chloroform or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate, filtered, evaporated and the product is purified by chromatography and/or crystallization. Temperatures are reported in degrees centigrade. Rf values were obtained on silica gel (mobile phase: dichloromethane/cyclohexane/ethyl acetate/methanol 3.2:3.2:1.6:2, unless otherwise indicated). EXAMPLE 1

A solution of 2.08 g of 3-(4-chlorobutyl)indole [or 2.52 g of 3-(4-bromobutyl)indole] and 1.65 g of 4-(2-thienyl)-1,2,3,6-tetrahydropyridine [hydrochloride, m.p. 242°; obtainable by reaction of 2-thienyl-Li with ethyl 4-oxo-1-piperidinecarboxylate to give ethyl 4-hydroxy-4-(2-thienyl)-1-piperidinecarboxylate, alkaline elimination of the protective group and dehydration with hydrochloric acid] in 10 ml of acetonitrile is stirred at 20° for 12 hours, worked up as usual and 3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]indole is obtained; hydrochloride ("T"), Rf 0.52.

The following are obtained analogously from the appropriate chloroalkyl or bromoalkyl or chlorothiaalkyl or bromothiaalkyl-indoles:

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-2-methylindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5-methoxyindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-6-methoxyindole, m.p. 158°

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5-methylthioindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-6-methylthioindole, hydrochloride, m.p. 208°

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-6-methylsulfinylindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-6-methylsulfonylindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-4-hydroxyindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5-hydroxyindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-6-hydroxyindole, m.p. 181°

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5-fluoroindole, hydrochloride, Rf 0.58

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5-chloroindole, hydrochloride, Rf 0.59

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-7-bromoindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5-trifluoromethylindole

3-[4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5-cyanoindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5,6-dimethylindole, hydrochloride, Rf 0.50 (chloroform:methanol=9 : 1)

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5,6-dimethoxyindole, m.p. 113°-115°

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5,6-dichloroindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5,6-methylenedioxyindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]indole, m.p. 86°-87+; hydrochloride, m.p. 182°-184°

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-2-methylindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5-methoxyindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-6-methoxyindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5-methylthioindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-6-methylthioindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-6-methylsulfinylindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-6-methylsulfonylindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl] -4-hydroxyindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5-hydroxyindole

3--[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-6-hydroxyindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5-fluoroindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5-chloroindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-7-bromoindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5-trifluoromethylindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5-cyanoindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5,6-dimethylindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5,6-dimethoxyindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5,6-dichloroindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5,6-methylenedioxyindole.

EXAMPLE 2

A mixture of 4.43 g of 3-(4-p-toluenesulfonyloxybutyl)indole and 3.3 g of 4-(2-thienyl)-1,2,3,6-tetrahydropyridine is heated to 130°. After the exothermic reaction has subsided and the mixture has cooled down, it is worked up as usual and "T" is obtained.

The following are obtained analogously from the appropriate tosylates:

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5-methylindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-6-methylindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5-butylindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5-ethoxyindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5-butoxyindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-6-butylthioindole

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5-bromoindole.

EXAMPLE 3

2.99 g of 3-(4-iodobutyl)indole, 1.65 g of 4-(2-thienyl)-1,2,3,6-tetrahydropyridine and 1.5 g of anhydrous potassium carbonate in 25 ml of n-butanol are boiled, with stirring, for 2 hours, allowed to cool, worked up as usual, and "T" is obtained.

EXAMPLE 4

A mixture of 1.88 g of 3-(4-aminobutyl)indole and 2.21 g of 1,5-dichloro-3-(2-thienyl)-2-pentene (obtainable by reduction of diethyl 3-(2-thienyl)-2-pentene-1,5-dioate with LiAlH₄ followed by reaction with SOCl₂) in 40 ml of acetone and 40 ml of water is boiled for 24 hours and worked up as usual. "T" is obtained.

The other compounds of the formula I indicated in Examples 1 and 2 are obtained analogously from the appropriate amines and the appropriate 1,5-dichloro-3-(2-thienyl)-2-pentenes.

EXAMPLE 5

1 g of NaBH₄ in 20 ml of water are added, with stirring, to a solution of 4.13 g of 1-[4-(3-indolyl)butyl]-4-(2-thienyl)pyridinium bromide [obtainable from 3-(4-bromobutyl)indole and 4-(2-thienyl)pyridine] in 50 ml of 1N NaOH, and the mixture is then stirred for 3 hours at 60°. After the usual work-up, "T" is obtained.

The other compounds of the formula I indicated in Examples 1 and 2 are obtained analogously by reduction of the appropriate pyridinium bromides.

EXAMPLE 6

A solution of 3.50 g of 3-[4-oxo-4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]indole [obtainable from 4-(3-indolyl)butyric acid and 4-(2-thienyl)-1,2,3,6-tetrahydropyridine in the presence of carbonyldiimidazole in THF] in 10 ml of THF is added dropwise, with stirring, to a suspension of 0.38 g of LiAlH₄ in 10 ml of THF. After the reaction has subsided, 5 ml of ethyl acetate are added, the mixture is worked up as usual and "T" is obtained.

The other compounds of the formula I indicated in Examples 1 and 2 are obtained analogously from the appropriate amides, for example

3-[4-oxo-4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-2-methylindole

3-[4-oxo-4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5-methoxyindole

3-[4-oxo-4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-6-methoxyindole [Rf 0.5 (chloroform:methanol=9:1)]

3-[4-oxo-4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5-methylthioindole

3-[4-oxo-4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-6-methylthioindole (m.p. 218°)

3-[4-oxo-4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-6-methylsulfinylindole

3-[4-oxo-4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-6-methylsulfonylindole

3-[4-oxo-4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-4-hydroxyindole

3-[4-oxo-4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5-hydroxyindole

3-[4-oxo-4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-6-hydroxyindole [Rf 0.48 (chloroform:methanol=9:1)]

3-[4-oxo-4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5-fluoroindole.

3-[4-oxo-4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-7-bromoindole

3-[4-oxo-4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5-trifluoromethylindole

3-[4-oxo-4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5,6-dimethylindole (m.p. 193°)

3-[4-oxo-4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl] -5,6-dimethoxyindole

3-[4-oxo-4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5,6-dichloroindole

3-[-4-oxo-4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5,6-methylenedioxyindole

3-[4-oxo-4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2thiabutyl]indole (m.p. 114°-115°)

EXAMPLE 7

4.76 g of 1-benzenesulfonyl 3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]indole [obtainable from 1-benzenesulfonyl-3-(4-chlorobutyl)indole and 4-(2-thienyl)-1,2,3,6-tetrahydropyridine] with 1 g of KOH in 7 ml of water and 14 ml of ethanol are boiled for 16 hours, the mixture is concentrated, worked up as usual and "T" is obtained.

EXAMPLE 8

3.80 g of 1-methyl-3-[4-hydroxy-4-(2-thienyl)-1-piperidyl)-2-thiabutyl]indole [obtainable by reaction of 1-methyl-3-(4-bromo-2-thiabutyl)indole with 4-piperidone, followed by reaction with 2-thienyl-Li and hydrolysis] are heated with 40 ml of 1N hydrochloric acid at 50° for

2 hours, the mixture is worked up as usual and 1-methyl-3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]indole is obtained.

EXAMPLE 9

6 ml of 30% H₂ O₂ are added to a boiling solution of 3.54 g of 3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]indole in 50 ml of ethanol, and the mixture is then boiled for 3 hours. After addition of a further 4 ml of the oxidizing agent, the mixture is boiled for 9 hours, cooled, worked up as usual and 4-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]indole S-oxide is obtained.

The following are obtainable analogously by oxidation of the appropriate thioethers:

3-[4-(4-(2-thienyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-2-methylindole S-oxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5-methoxyindole S-oxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-6-methoxyindole S-oxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5-methylsulfinylindole S-oxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-6-methylsulfinylindole S-oxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-4-hydroxyindole S-oxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5-hydroxyindole S-oxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-6-hydroxyindole S-oxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5-fluoroindole S-oxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5-chloroindole S-oxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-7-bromoindole S-oxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl] -5-trifluoromethylindole S-oxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5-cyanoindole S-oxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5,6-dimethylindole S-oxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5,6-dimethoxyindole S-oxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5,6-dichloroindole S-oxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5,6-methylenedioxyindole S-oxide.

EXAMPLE 10

9 ml of 30% H₂ O₂ are added to a solution of 3.54 g of 3.-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]indole in 20 ml of acetic acid, and the mixture is boiled for 90 minutes. After the usual work-up, 3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]indole S,S-dioxide is obtained.

The following are obtainable analogously by oxidation of the appropriate thioethers:

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-2-methylindole S,S-dioxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5-methoxyindole S,S-dioxide

3-[4- -(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-6-methoxyindole S,S-dioxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5-methylsulfonylindole S,S-dioxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl] -6-methylsulfonylindole S,S-dioxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-4-hydroxyindole S,S-dioxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5-hydroxyindole S,S-dioxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-6-hydroxyindole S,S-dioxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5-fluoroindole S,S-dioxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5-chloroindole S,S-dioxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-7-bromoindole S,S-dioxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5-trifluoromethylindole S,S-dioxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5-cyanoindole S,S-dioxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5,6-dimethylindole S,S-dioxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5,6-dimethoxyindole S,S-dioxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5,6-dichloroindole S,S-dioxide

3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5,6-methylenedioxyindole S,S-dioxide.

EXAMPLE 11

A mixture of 4.03 g of 3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-6-methoxyindole hydrochloride and 3.5 g of pyridine hydrochloride is stirred at 160° for 3 hours. After the usual work-up, 3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-6-hydroxyindole of m.p. 181° is obtained.

The examples which follow relate to pharmaceutical formulations which contain amines of the formula I or their acid addition salts:

EXAMPLE A Tablets

A mixture of 1 kg of "T", 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed to form tablets in a customary manner such that each tablet contains 10 mg of active compound.

EXAMPLE B Coated tablets

Tablets are formed by compression in analogy to Example A and these are then coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

EXAMPLE C Capsules

2 kg of "T" are filled into hard gelatine capsules in a customary manner such that each capsule contains 20 mg of the active compound.

EXAMPLE D Ampoules

A solution of 1 kg of "T" in 30 Liters of double-distilled water is sterilized by filtration, filled into ampoules, freeze-dried under sterile conditions and closed sterile. Each ampoule contains 10 mg of active compound.

In analogy, tablets, coated tablets, capsules and ampoules can be obtained which contain one or more of the other active compounds of the Formula I and/or their physiologically acceptable acid addition salts.

The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples. From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. 

What is claimed is:
 1. An indole derivative of the formula ##STR10## wherein Ind is 3-indolyl or 3-indolyl substituted once or twice by alkyl, O-alkyl, S-alkyl, SO-alkyl, SO₂ -alkyl, OH, F, Cl, Br, CF₃ or CN or by a methylenedioxy group;A is --(CH₂)₄ -- or --CH₂ --L--CH₂ CH₂ --; L is --S--, --SO-- or --SO₂ --; Th is 2- or 3-thienyl; and wherein the alkyl groups each have 1-4 C atoms; or a physiologically acceptable acid addition salt thereof.
 2. A compound of claim 1, wherein Ind is 3-indolyl, methyl-3-indolyl, dimethyl-3-indolyl, methoxy-3-indolyl, dimethoxy-3-indolyl, hydroxy-3-indolyl, dihydroxy-3-indolyl, fluoro-3-indolyl, chloro-3-indolyl, dichloro-3-indolyl, bromo-3-indolyl, cyano-3-indolyl or methylenedioxy-3-indolyl, each substituent being in the 5-or 6-position.
 3. A compound of claim 1, wherein Ind is 3-indolyl, 5- or 6-methyl-3-indolyl, 5,6-dimethyl-3-indolyl, 5- or 6-methoxy-3-indolyl, 5,6-dimethoxy-3-indolyl, 6-methylthio-3-indolyl, 6-hydroxy-3-indolyl, 5-chloro-3-indolyl or 5-fluoro-3-indolyl.
 4. A compound of claim 1, wherein Ind is 3-indolyl or 5,6-dimethoxy-3-indolyl.
 5. A compound of claim 1, wherein A is --(CH₂)₄ --.
 6. A compound of claim 1, wherein A is --CH₂ --L--CH₂ CH₂ --.
 7. A compound of claim 1, wherein A is --CH₂ --S--CH₂ CH₂ --.
 8. A compound of claim 1, wherein Th is 2-thienyl.
 9. A compound of claim 1, wherein Ind is 3-indolyl, 5,6-dimethyl-3-indolyl, 6-methoxy-3-indolyl, 5,6-dimethoxy-3-indolyl, 6-methylthio-3-indolyl, 6-hydroxy-3-indolyl, 5-fluoro-3-indolyl or 5-chloro-3-indolyl, A is --(CH₂)₄ -- or --CH₂ --S--CH₂ CH₂ --, and Th is 2-thienyl.
 10. A compound of claim 1, wherein Ind is 3-indolyl or 5,6-dimethoxy-3-indolyl, A is --(CH₂)₄ -- or --CH₂ --S--CH₂ CH₂ --, and Th is 2-thienyl.
 11. A compound of claim 1, wherein Ind is 3-indolyl, A is --(CH₂)₄ -- or --CH₂ --S--CH₂ CH₂ -- and Th is 2-thienyl.
 12. A compound of claim 1, wherein Ind is 3-indolyl or 5,6-dimethoxy-3-indolyl, A is --(CH₂)₄ -- and Th is 2-thienyl.
 13. 3-[4-(4-(2-Thienyl)-1,2,3,6-tetrahydropyridyl)butyl]indole; 3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-5,6-dimethoxyindole; or 3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]indole, each a compound of claim
 1. 14. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
 15. A composition comprising 0.2-500 mg of a compound of claim 1 and a pharmaceutically acceptable carrier. 